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Kondrashova O , Topp M , Nesic K , Lieschke E , Ho GY , Harrell MI , Zapparoli GV , Hadley A , Holian R , Boehm E , Heong V , Sanij E , Pearson RB , Krais JJ , Johnson N , McNally O , Ananda S , Alsop K , Hutt KJ , Kaufmann SH , Lin KK , Harding TC , Traficante N , deFazio A , McNeish IA , Bowtell DD , Swisher EM , Dobrovic A , Wakefield MJ , Scott CL
Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Nat Commun. 2018 Sep 28;9(1) :3970
PMID: 30266954    PMCID: PMC6162272   
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Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
2041-1723 Kondrashova, Olga ORCID: http://orcid.org/0000-0003-0022-5149 Topp, Monique Nesic, Ksenija Lieschke, Elizabeth Ho, Gwo-Yaw Harrell, Maria I Zapparoli, Giada V Hadley, Alison Holian, Robert Boehm, Emma Heong, Valerie Sanij, Elaine Pearson, Richard B ORCID: http://orcid.org/0000-0001-5919-5090 Krais, John J Johnson, Neil McNally, Orla Ananda, Sumitra Alsop, Kathryn Hutt, Karla J Kaufmann, Scott H ORCID: http://orcid.org/0000-0002-4900-7145 Lin, Kevin K Harding, Thomas C Traficante, Nadia Australian Ovarian Cancer Study (AOCS) deFazio, Anna McNeish, Iain A ORCID: http://orcid.org/0000-0002-9387-7586 Bowtell, David D Swisher, Elizabeth M Dobrovic, Alexander Wakefield, Matthew J ORCID: http://orcid.org/0000-0001-6624-4698 Scott, Clare L ORCID: http://orcid.org/0000-0002-3689-5956 P50 CA083636/CA/NCI NIH HHS/United States Journal Article England Nat Commun. 2018 Sep 28;9(1):3970. doi: 10.1038/s41467-018-05564-z.